Improvement of Gut Microbiota by Inhibition of P38 Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Rats with Severe Acute Pancreatitis

Wan, Yong; Bian, Zhong-Zheng; Pan, Xinting

doi:10.12659/msm.914538

Cited by 23 publications

(23 citation statements)

References 24 publications

(27 reference statements)

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“…19 Other studies in animal models also showed that improvements in the gut microbiota or supplementation with its metabolites ameliorated pancreatic injury by maintaining gut homeostasis. [20][21][22][23] Here, we observed that depletion of the gut microbiota reduced pancreatic damage and suppressed the systemic inflammatory response, while FMT reversed this process. This finding was consistent with previous studies that showed a protective effect of antibiotics on AP, and this protective effect was weakened after transplanting gut commensal bacteria.…”

Section: Discussionmentioning

confidence: 55%

The interplay between the gut microbiota and NLRP3 activation affects the severity of acute pancreatitis in mice

et al. 2020

Gut Microbes

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Early dysbiosis of the gut microbiota is associated with the severity of acute pancreatitis (AP), although the underlying mechanism is unclear. Here, we investigated the role of crosstalk between NLRP3 and the gut microbiota in the development of AP utilizing gut microbiota deficient mice, as well as NLRP3 knockout (KO) mouse models. Pancreatic damage and systemic inflammation were improved in antibiotic-treated (Abx) and germ-free (GF) mice, accompanied by weakened activity of the intestinal NLRP3 inflammasome. Interestingly, fecal microbiota transplantation (FMT) reactivated the intestinal NLRP3 inflammasome and exacerbated the disease in Abx and GF mice. Although the gut barrier in GF and Abx mice was disrupted, gut microbiota deficiency ameliorated the severity of AP, probably due to the reduction in bacterial translocation from the gut to the pancreas. The composition of the gut microbiota was significantly different between NLRP3 KO mice and wild-type (WT) mice at baseline, and there were alterations in response to the induction of AP. While a dramatic shift in the gut microbiota with overgrowth of Escherichia-Shigella was observed in WT mice suffering from AP, there was no significant change in NLRP3 KO mice with or without AP, suggesting that NLRP3 deficiency counteracts AP-induced microbial disturbance. With a strengthened gut barrier and decreased systemic inflammation, NLRP3 KO mice showed less severe AP, as revealed by reduced pancreatic neutrophilic infiltration and necrosis. Taken together, these results identified the bidirectional modulation between the gut microbiota and NLRP3 in the progression of AP, which suggests the interplay of the host and microbiome during AP.

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Section: Discussionmentioning

confidence: 55%

The interplay between the gut microbiota and NLRP3 activation affects the severity of acute pancreatitis in mice

et al. 2020

Gut Microbes

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“…Recent studies indicate that intestinal microbiota participate in the occurrence and development of pancreatitis [7,8]. Our group has previously reported dramatically changed intestinal microbiota in rats with pancreatitis, and we were able to improve the intestinal microbiota imbalance of theses rats with anti-inflammatory therapy [9]. Evidence also indicates that bile acids are involved in the development of AP, but the exact mechanisms underlying this association are unclear, especially in non-biliary pancreatitis [10].…”

Section: Introductionmentioning

confidence: 77%

“…Samples were analyzed by 16S rDNA gene sequencing, the details of which we have reported previously [ 9 ] . Operational taxonomic units (OTUs) that reached 97% similarity and Shannon index were used for α -diversity estimations.…”

Section: Analysis Of Intestinal Microbiotamentioning

confidence: 99%

Bile acid supplementation improves murine pancreatitis in association with the gut microbiota

Wan

Pan

Sun

2020

Preprint

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Disorders of bile acids (BAs) are closely related to the development of liver and intestinal diseases, including acute pancreatitis (AP). However, the mechanism underlying the involvement of BAs in AP development remains unclear. We used intraperitoneal injection of cerulein to construct AP mouse models. These mice had significantly reduced tauroursodeoxycholic acid (TUDCA) and an imbalance of intestinal microbiota, based on 16S rDNA gene sequencing. To explore the role of AP-induced intestinal microbiota changes in the development of AP, we transplanted stool obtained from AP mice to antibiotic-treated, microbiota-depleted healthy mice. Microbiota-depleted mice presented injury to the intestinal barrier function and pancreas. Additionally, microbiota depletion reduced AP-associated pancreatic injury. This indicated that the gut microbiota may worsen AP. As TUDCA was deficient in AP mice, we gavaged AP mice with it, and evaluated subsequent expression changes in the bile acid signaling receptors farnesoid-x-receptor (FXR) and its target gene fibroblast growth factor (FGF) 15. These were downregulated, and pancreatic and intestinal barrier function injury were mitigated. Similar results were found in microbiota-depleted AP without BA treatment. However, we did not observe further downregulation of the FXR signaling pathway in microbiota-depleted AP mice given TUDCA, indicating that improvement of pancreatitis by TUDCA may be associated with gut microbiota. Our analysis of changes to the gut microbiota in AP indicated that Lactobacilli may be the key contributors.Taken together, our study shows that supplementation with BAs could improve bile acid-FXR-FGF15 signaling, and reduce pancreatic and intestinal injury, and that this effect may be associated with the gut microbiota.

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“…In this study, modafinil treatment significantly reduces IL-6, TNF-α and CRP levels in the serum of AP rats, replying that modafinil might repress pro-inflammatory process to some extent. The studies have demonstrated that inflammation response in AP could be regulated by p38 MAPK pathway or microRNA, which implied that modafinil might also reduce inflammation through affecting aforementioned substance (Gu et al 2019;Wan et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Modafinil ameliorated pancreatic injury and inflammation through upregulating SNIP1

Qin

et al. 2020

gpb

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Acute pancreatitis (AP) is the inflammatory response of the exocrine pancreas to various causes. Modafinil has significant anti-inflammation and anti-oxidation effects. No experiment has assessed the effects of modafinil on AP. Thus, the study aims to study the effects of modafinil on AP and its potential mechanism in vivo and vitro. 5% sodium taurocholate was retrograde injected into pancreatic duct to establish AP rat model. The severity of AP was detected by H&E staining, serum amylase and lipase levels. The inflammation, oxidative stress and apoptosis were detected separately by ELISA, MDA and SOD kits, tunnel staining and Western blotting in rats. Besides, SNIP1 expression was analyzed by qPCR and Western blotting. In vivo, AR42J cells were stimulated by cerulein and lipopolysaccharide to establish AP cell model. Flow cytometry examined cell apoptosis. After the plasmids silencing SNIP1 were transfected into AP cells, the inhibitory effects of modafinil on inflammation, oxidative stress and apoptosis were significantly reversed. The results indicated that modafinil showed significant curative and therapeutic effects by regulating SNIP1 levels.

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Improvement of Gut Microbiota by Inhibition of P38 Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Rats with Severe Acute Pancreatitis

Cited by 23 publications

References 24 publications

The interplay between the gut microbiota and NLRP3 activation affects the severity of acute pancreatitis in mice

The interplay between the gut microbiota and NLRP3 activation affects the severity of acute pancreatitis in mice

Bile acid supplementation improves murine pancreatitis in association with the gut microbiota

Modafinil ameliorated pancreatic injury and inflammation through upregulating SNIP1

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